Modulation of potassium channel function confers a hyperproliferative invasive phenotype on embryonic stem cells.
Ion transporters, and the resulting voltage gradients and electric fields, have been implicated in embryonic development and regeneration. These biophysical signals are key physiological aspects of the microenvironment that epigenetically regulate stem and tumor cell behavior. Here, we identify a previously unrecognized function for KCNQ1, a potassium channel known to be involved in human Romano-Ward and Jervell-Lange-Nielsen syndromes when mutated. Misexpression of its modulatory wild-type beta-subunit XKCNE1 in the Xenopus embryo resulted in a striking alteration of the behavior of one type of embryonic stem cell: the pigment cell lineage of the neural crest. Depolarization of embryonic cells by misexpression of KCNE1 non-cell-autonomously induced melanocytes to overproliferate, spread out, and become highly invasive of blood vessels, liver, gut, and neural tube, leading to a deeply hyperpigmented phenotype. This effect is mediated by the up-regulation of Sox10 and Slug genes, thus linking alterations in ion channel function to the control of migration, shape, and mitosis rates during embryonic morphogenesis. Taken together, these data identify a role for the KCNQ1 channel in regulating key cell behaviors and reveal the molecular identity of a biophysical switch, by means of which neoplastic-like properties can be conferred upon a specific embryonic stem cell subpopulation.
Morokuma
Junji
J
Center for Regenerative and Developmental Biology, Forsyth Institute, and Department of Developmental Biology, Harvard School of Dental Medicine, 140 The Fenway, Boston, MA 02115, USA.
Blackiston
Douglas
D
Adams
Dany S
DS
Seebohm
Guiscard
G
Trimmer
Barry
B
Levin
Michael
M
D000818:Animals; D049109:Cell Proliferation; D053595:Embryonic Stem Cells / Q000166:cytology*; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics; D008544:Melanocytes; D009369:Neoplasms / Q000209:etiology / Q000473:pathology; D010641:Phenotype; D015221:Potassium Channels / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics; D055757:SOXE Transcription Factors / Q000235:genetics; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics; D014162:Transfection; D015854:Up-Regulation; D014981:Xenopus
C489622:KCNE1 protein, human; D051657:KCNQ1 Potassium Channel; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; C000604407:SNAI1 protein, human; D055757:SOXE Transcription Factors; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors